Effectiveness of Sequential Psychological and Medication Therapies for Insomnia Disorder: A Randomized Clinical Trial

Abstract

Importance: Despite evidence of efficacious psychological and pharmacologic therapies for insomnia, there is little information about what first-line treatment should be and how best to proceed when initial treatment fails.

Objective: To evaluate the comparative efficacy of 4 treatment sequences involving psychological and medication therapies for insomnia and examine the moderating effect of psychiatric disorders on insomnia outcomes.

Design, setting, and participants: In a sequential multiple-assignment randomized trial, patients were assigned to first-stage therapy involving either behavioral therapy (BT; n = 104) or zolpidem (zolpidem; n = 107), and patients who did not remit received a second treatment involving either medication (zolpidem or trazodone) or psychological therapy (BT or cognitive therapy [CT]). The study took place at Institut Universitaire en Santé Mentale de Québec, Université Laval, Québec City, Québec, Canada, and at National Jewish Health, Denver, Colorado, and enrollment of patients took place from August 2012 through July 2017.

Main outcomes and measures: The primary end points were the treatment response and remission rates, defined by the Insomnia Severity Index total score.

Results: Patients included 211 adults (132 women; mean [SD] age, 45.6 [14.9] years) with a chronic insomnia disorder, including 74 patients with a comorbid anxiety or mood disorder. First-stage therapy with BT or zolpidem produced equivalent weighted percentages of responders (BT, 45.5%; zolpidem, 49.7%; OR, 1.18; 95% CI, 0.60-2.33) and remitters (BT, 38.03%; zolpidem, 30.3%; OR, 1.41; 95% CI, 0.75-2.65). Second-stage therapy produced significant increases in responders for the 2 conditions, starting with BT (BT to zolpidem, 40.6% to 62.7%; OR, 2.46; 95% CI, 1.14-5.30; BT to CT, 50.1% to 68.2%; OR, 2.09; 95% CI, 1.01-4.35) but no significant change following zolpidem treatment. Significant increase in percentage of remitters was observed in 2 of 4 therapy sequences (BT to zolpidem, 38.1% to 55.9%; OR, 2.06; 95% CI, 1.04-4.11; zolpidem to trazodone, 31.4% to 49.4%; OR, 2.13; 95% CI, 0.91-5.00). Although response/remission rates were lower among patients with psychiatric comorbidity, treatment sequences that involved BT followed by CT or zolpidem followed by trazodone yielded better outcomes for patients with comorbid insomnia. Response and remission rates were well sustained through the 12-month follow-up.

Conclusions and relevance: Behavioral therapy and zolpidem medication produced equivalent response and remission rates. Adding a second treatment produced an added value for those whose insomnia failed to remit with initial therapies.

Trial registration: ClinicalTrials.gov Identifier: NCT01651442.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Morin has served as a consultant for Abbot, Eisai, Merck, Philips, and Weight Watchers and received research support from Idorsia and Canopy Health. Dr Edinger has received research support from Merck and Philips/Respironics. Ms Cartwright received research grant support from the National Institutes of Health, Janssen, Jazz Axsome, and Reveal Biosensors and served as a consultant to Eisai, Ferring, Galderma, Harmony Biosciences, Idorsia, Jazz, Janssen, Takeda, Merck, Neurocrine, Pernix, and Physician’s Seal. Dr Krystal reported grants from the National Institutes of Health, Patient-Centered Outcomes Research Institute, Axsome, and Reveal Biosensors; grants and personal fees from Janssen, Jazz, personal fees from Evecxia; and personal fees from Sage, Ferring, Galderma, Harmony Biosciences, Eisai, Idorsia, Neurocrine, Merck, and Takeda outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Patient Flowchart

The 54 patients randomized to second-stage therapy included all patients not in remission after first-stage therapy who accepted second randomization and a few patients who did not complete first-stage treatment according to study protocol but were available for second treatment.

Figure 2.. Response and Remission Rates After Stage 1 and Stage 2 Therapies

aP <.05.

Figure 3.. Response and Remission Rates According to Condition and Assessment

A, Standard errors are 0.06 at post1 and ranged from 0.07 to 0.09 for latter assessments. B, Standard errors are 0.05 at post1 and ranged from 0.07 to 0.09 for latter assessments. BT indicates behavioral therapy; CT, cognitive therapy; FU, follow-up; ISI, Insomnia Severity Index; TRAZ, trazodone; ZOL, zolpidem.